Phenotypic heterogeneity seen within specific genetic disorders provides an opportunity to examine the mutational events responsible for the observed clinical diversity. Patients with mucopolysaccharidoses IH, IH/S or IS all have a deficiency of Alpha-L-iduronidase, but the abnormality of enzymatic activity alone is insufficient to explain the wide differences in severity of symptoms in the three major variants of the disorder. As has been demonstrated for other lysosomal disorders, it is likely that a description of the effect of mutations on the biosynthesis, intracellular compartmentalization and degradation of Alpha-L-iduronidase will shed light on the significance of transcriptional, translational or other protein processing abnormalities that result in the neurologic and non-neurologic features of these diseases. The aim of these studies is to define the abnormal biochemistry of this group of mucopolysaccharidoses and to characterize the factors responsible for variations in symptoms among patients in molecular terms. To achieve this goal, the Alpha-L-iduronidase was purified from human placenta. This has allowed the study of both the biochemical and immunological properties of this enzyme. Pulse-chase and western analyses of Alpha-iduronidase using normal and mutant cell lines were performed to elucidate protein polymorphisms that may prove to be characteristic of the individual phenotypes. Studies dealing with the isolation of the gene are in progress. The isolation of cDNA clones encoding normal human Alpha-L-iduronidase permit a more detailed study of the chromosomal locus, gene variants, as well as the factors controlling expression of the gene. These studies allow formulation of therapeutic strategies utilizing both gene product and recombinant DNA approaches.